The hematopoietic system is one of the most sensitive tissues in the body to the effects of ionizing radiation and chemotherapy. Acute hematopoietic stem cell (HSC) injury results in the suppression of hematopoiesis and predisposes to the development of hematologic disorders, including leukemia. Therefore, research endeavors aimed at regenerating HSCs have the potential to significantly improve outcomes following radiation exposure. HSCs reside in functional niches within the bone marrow, where their self-renewal and differentiation are modulated by cells that comprise the hematopoietic microenvironment. Endothelial cells (ECs) are a critical component of this microenvironment, and we have previously shown that ECs are capable of mitigating HSC- lethal doses of radiation. Our recent data indicate that ECs both regenerate HSCs and enhance DNA repair; however, the EC-derived signals responsible are not known. The goal of this proposal is to understand how ECs promote the regeneration and repair of HSCs after irradiation. To accomplish this, I will 1) determine the extent to which EC-mediated hematopoietic regeneration mitigates long-term HSC damage and dysfunction; and 2) identify EC-derived factors that promote the regeneration of radiation-damaged HSCs. Taken together, the results from these experiments will improve our mechanistic understanding of HSC regeneration and provide novel therapeutic options for enhancing hematopoietic recovery after radiation injury.